The need to transform economic models to implement a circular use of resources is crucial due to the current waste accumulation crisis. New waste-to-resource alternatives are constantly emerging to close material loops; therefore, tools are needed to identify the best synergies to upcycle waste. An approach has been developed to identify and assess waste-to-resource processing routes not currently implemented at the industrial level to valorize waste. The proposed framework consists of several interconnected modules that include ontologies for knowledge management, graph theory and short-path algorithms for the generation of paths and pre-assessment of processes, a Mixed-Integer Linear Programming (MILP) model for superstructure optimization; and the rigorous design, simulation, and optimization exclusively of those alternatives that show the best performance in previous steps. A case study for the treatment of mixed plastic waste reveals chemical recycling and the pro- duction of pyrolytic fuels as tentatively favorable options, both environmentally and economically.